B. QUALITY CHANGES – B.II FINISHED PRODUCT – B.II.e) Container closure system (obsolete version)

This is an archived version. Please see the current version here: Q. QUALITY CHANGES – Q.II. FINISHED PRODUCT – Q.II.e) Container closure system

B.II.e.1 Change in immediate packaging of the finished product

B.II.e.2 Change in the specification parameters and/or limits of the immediate packaging of the finished product

B.II.e.3 Change in test procedure for the immediate packaging of the finished product

B.II.e.4 Change in shape or dimensions of the container or closure (immediate packaging)

B.II.e.5 Change in pack size of the finished product

B.II.e.6 Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used))

B.II.e.7 Change in supplier of packaging components or devices (when mentioned in the dossier)

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B.II.e.1 Change in immediate packaging of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Qualitative and quantitative composition
1. Solid pharmaceutical forms	1, 2, 3	1, 2, 3, 4, 6	IA
2. Semi-solid and non-sterile liqui pharmaceutical forms		1, 2, 3, 5, 6	IB
3. Sterile medicinal products and biological/ immunological medicinal products.			II
4. The change relates to a less protective pack where there are associated changes in storage conditions and/or reduction in shelf life.			II
b) Change in type of container or addition of a new container
1. Solid, semi-solid and non-sterile liquid pharmaceutical forms		1, 2, 3, 5, 6, 7	IB
2. Sterile medicinal products and biological/ immunological medicinal products			II
3. Deletion of an immediate packaging container that does not lead to the complete deletion of a strength or pharmaceutical form	4	1, 8	IA
Conditions
1. The change only concerns the same packaging/container type (e.g. blister to blister).
2. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties.
3. Relevant stability studies have been started under ICH/VICH conditions and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant at time of implementation. However, if the proposed packaging is more resistant than the existing packaging e.g. thicker blister packaging, the three months’ stability data do not yet have to be available. These studies must be finalised and the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
4. The remaining product presentation(s) must be adequate for the dosing instructions and treatment duration as mentioned in the summary of product characteristics.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), including revised product information as appropriate.
2. Appropriate data on the new packaging (comparative data on permeability e.g. for O2, CO2 moisture).
3. Where appropriate, proof must be provided that no interaction between the content and the packaging material occurs (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the pack), including confirmation that the material complies with relevant pharmacopoeial requirements or legislation of the Union on plastic material and objects in contact with foodstuffs.
4. A declaration that the required stability studies have been started under ICH/VICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
5. The results of stability studies that have been carried out under ICH/VICH conditions, on the relevant stability parameters, on at least two pilot or industrial scale batches, covering a minimum period of 3 months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
6. Comparative table of the current and proposed immediate packaging specifications, if applicable.
7. Samples of the new container/closure where applicable (see NTA, Requirements for samples in the Member States/EMA).
8. Declaration that the remaining pack-size(s) is/are consistent with the dosage regimen and duration of treatment and adequate for the dosing instructions as approved in the summary of product characteristics.
Note: For B.II.e.1.b) applicants are reminded that any change which results in a “new pharmaceutical form” requires the submission of an Extension application.

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B.II.e.2 Change in the specification parameters and/or limits of the immediate packaging of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Tightening of specification limits	1, 2, 3, 4	1, 2	IA
b) Addition of a new specification parameter to the specification with its corresponding test method	1, 2, 5	1, 2, 3, 4, 6	IA
c) Deletion of a non-significant specification parameter (e.g. deletion of an obsolete parameter)	1, 2	1, 2, 5	IA
d) Addition or replacement of a specification parameter as a result of a safety or quality issue		1, 2, 3, 4, 6	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a type II variation procedure).
2. The change does not result from unexpected events arising during manufacture
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. Comparative table of current and proposed specifications.
3. Details of any new analytical method and validation data, where relevant.
4. Batch analysis data on two batches of the immediate packaging for all specification parameters.
5. Justification/risk assessment showing that the parameter is non-significant or that it is obsolete.
6. Justification of the new specification parameter and the limits.

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B.II.e.3 Change in test procedure for the immediate packaging of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor changes to an approved test procedure	1, 2, 3	1, 2	IA
b) Other changes to a test procedure (including replacement or addition)	1, 3, 4	1, 2	IA
c) Deletion of a test procedure if an alternative test procedure is already authorised	5	1	IA
Conditions
1. Appropriate validation studies have been performed in accordance with the relevant guidelines and validation studies show that the updated test procedure is at least equivalent to the former test procedure.
2. The method of analysis should remain the same (e.g. a change in column length or temperature, but not a different type of column or method).
3. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
4. The active substance/ finished product is not biological/immunological.
5. An alternative test procedure is already authorised for the specification parameter and this procedure has not been added through IA/IA(IN) notification.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), including a description of the analytical methodology, a summary of validation data.
2. Comparative validation results or if justified comparative analysis results showing that the current test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.

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B.II.e.4 Change in shape or dimensions of the container or closure (immediate packaging)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Non-sterile medicinal products	1, 2, 3	1, 2, 4	IA
b) The change in shape or dimensions concerns a fundamental part of the packaging material, which may have a significant impact on the delivery, use, safety or stability of the finished product			II
c) Sterile medicinal products		1, 2, 3, 4	IB
Conditions
1. No change in the qualitative or quantitative composition of the container.
2. The change does not concern a fundamental part of the packaging material, which affects the delivery, use, safety or stability of the finished product.
3. In case of a change in the headspace or a change in the surface/volume ratio, stability studies in accordance with the relevant guidelines have been started and relevant stability parameters have been assessed in at least two pilot scale (three for biological/immunological medicinal products) or industrial scale batches and at least three months (six months for biological/immunological medicinal products) stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate) ,including description, detailed drawing and composition of the container or closure material, and including revised product information as appropriate.
2. Samples of the new container/closure where applicable (see NTA, Requirements for samples in the Member States).
3. Re-validation studies have been performed in case of sterile products terminally sterilised. The batch numbers of the batches used in the re-validation studies should be indicated, where applicable.
4. In case of a change in the headspace or a change in the surface/volume ratio, a declaration that the required stability studies have been started under ICH/VICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation for a Type IA notification and time of submission of a Type IB notification, and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).

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B.II.e.5 Change in pack size of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Change in the number of units (e.g. tablets, ampoules, etc.) in a pack
1. Change within the range of the currently approved pack sizes	1, 2	1, 3	IA_IN
2. Change outside the range of the currently approved pack sizes		1, 2, 3	IB
b) Deletion of pack size(s)	3	1, 2	IA
c) Change in the fill weight/fill volume of sterile multidose (or single-dose, partial use) parenteral medicinal products, including biological/ immunological medicinal products.			II
d) Change in the fill weight/fill volume of non- parenteral multi-dose (or single-dose, partial use) products		1, 2, 3	IB
Conditions
1. New pack size should be consistent with the posology and treatment duration as approved in the Summary of Product Characteristics.
2. The primary packaging material remains the same.
3. The remaining product presentation(s) must be adequate for the dosing instructions and treatment duration as mentioned in the Summary of Product Characteristics.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate) including revised product information as appropriate.
2. Justification for the new/remaining pack-size, showing that the new/remaining size is/are consistent with the dosage regimen and duration of treatment as approved in the summary of product characteristics
3. Declaration that stability studies will be conducted in accordance with the relevant guidelines for products where stability parameters could be affected. Data to be reported only if outside specifications (with proposed action).
Note: For B.II.e.5.c) and d), applicants are reminded that any changes to the ‘strength’ of the medicinal product require the submission of an Extension application.

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B.II.e.6 Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used))	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Change that affects the product information	1	1	IA_IN
b) Change that does not affect the product information	1	1	IA
Conditions
1. The change does not concern a part of the packaging material, which affects the delivery, use, safety or stability of the finished product.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), including revised product information as appropriate.

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B.II.e.7 Change in supplier of packaging components or devices (when mentioned in the dossier)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Deletion of a supplier	1	1	IA
b) Replacement or addition of a supplier	1, 2, 3, 4	1, 2, 3	IA
c) Any change to suppliers of spacer devices for metered dose inhalers			II
Conditions
1. No deletion of packaging component or device.
2. The qualitative and quantitative composition of the packaging components/device and design specifications remain the same.
3. The specifications and quality control method are at least equivalent.
4. The sterilisation method and conditions remain the same, if applicable.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. For devices for medicinal products for human use, proof of CE marking.
3. Comparative table of current and proposed specifications, if applicable.